The number of persons complaining of arthropathy has been surely increased in the aging society. It is very important to perform early diagnosis or screening of diseases such as osteoarthritis and rheumatoid arthritis as typical articular diseases or exact prognostic analysis of patients, and the treatment thereof leads to the improve in quality of life of many aged persons. However, satisfactory diagnostic and therapeutic methods have not yet been established.
The articular cartilage is a tissue that comprises a small number of chondrocytes covering the movable surface of the joint and a large number of extracellular matrix. Blood vessels or nerves are not distributed therein, and nutrients are supplied mainly from a synovial fluid produced from the synovial membrane covering the inner surface of the joint. Further, it is not only avascular but also exhibits strong resistance to invasion of blood vessels from the peripheral tissues rich in vasoganglion. Chondrocytes intricately control both of synthesis and degradation of extracellular matrix to play a major role in maintaining homeostasis of extracellular matrix. Chemical factors such as cytokines and growth factors and dynamic factors such as weight loading act on chondrocytes and change the balance of both the synthesis and the degradation of extracellular matrix to influence metabolism of extracellular matrix.
Osteoarthritis is caused by the aging or mechanical stresses to thereby induce disruption of the articular cartilage surface accompanied by growth of new cartilages around joints, deformation of joints and failure of adaptability and to lead to inflammation of synovial membranes of joints. The osteoarthritis is a monoarthritis disease with delayed denaturation of the articular cartilage, and characteristics thereof are often pains and functional loss (Manek M. J. and Lane N. E., Am. Fam. Physician, 61, 1795-1804, 2000).
In rheumatoid arthritis, inflammatory cells invade synovial membranes because of immunological abnormality or infectious diseases, and the growth of synovial fibroblasts progresses according to angiogenesis to form an inflammatory synovial granulation tissue called pannus. When the pannus is formed, destruction of bones or cartilages proceeds to cause irreversible disorder in joints. During the destruction of bones or cartilages, various extracellular matrix present in large quantities, such as collagen and proteoglycan are degraded.
In articular diseases such as osteoarthritis and rheumatoid arthritis, the synovitis and the destruction of extracellular matrix lead to the functional loss of articular cartilages.
Osteoarthritis and rheumatoid arthritis are quite different diseases, but have many common points in the articular cartilage destruction mechanism. Many types of matrix metalloproteases are produced and secreted in the articular synovial fluid and articular portions such as a synovial membrane and a cartilage, and matrix metalloproteases are excessively detected in the articular portions. Matrix metalloproteases degrade many types of extracellular matrix, which is one cause of articular destruction. They are produced not only from inflamed synovial membranes, macrophages and neutrophils but also from chondrocytes. This production is controlled by various cytokines produced or secreted in the same articular portions, superoxide anion, nitric oxide, prostaglandins, growth factors and the like. It has been reported that these induce the production of matrix metalloproteases from synovial cells and chondrocytes to promote degradation of extracellular matrix.
From these reports, it is considered that osteoarthritis and rheumatoid arthritis as well as arthritic diseases such as systemic lupus erythematosus which is an cryptogenic disease with an inflammatory tissue disorder caused by appearance of autoantibody and tissue deposition of an antigen-antibody complex and in which arthropathy occurs at a high rate, arthropathy, psoriatic arthritis leading to bone destruction with synovial membrane growth complicated in psoriatic patients, discopathy in which destruction of extracellular matrix of the intervertebral disc disease is observed and acute crystalline synovitis (gout, pseudogout) (Ryumachi Gaku, compiled by Hirohata Kazushi et al., Dobun Shoin, 1989) can be treated by inhibiting growth of the synovial membrane or destruction of cartilages.
In the pharmacotherapy of rheumatoid arthritis, various non-steroidal antiinflammatory agents, steroidal agents such as prednisolone and antirheumatic agents such as methotrexate have been so far used mainly to reduce pains and inflammation of joints (Chiryo, 78, 3553-3558, Nanzando, 1996). In osteoarthritis, various non-steroidal antiinflammatory agents, analgesic agents, hyaluronic acid pharmaceutical preparations as an intraarticular injection and the like have been administered to remove pains and inflammation. Hyaluronic acid which inhibits destruction of cartilages has been used as an agent for protecting cartilage (Creamer P., J. Rheum., 20, 1461-1464, 1993, Arthritis Rheum., 43, 1905-1915, 2000). Further, physical therapy and operative treatments such as osteotomy and artificial joint replacement have been carried out. Non-steroidal antiinflammatory agents and steroidal agents such as prednisolone are used in systemic lupus erythematosus, non-steroidal antiinflammatory agents and sulfasalazine as an antirheumatic drug in ankylotic arthropathy, non-steroidal antiinflammatory agents, antirheumatic drugs and steroidal intraarticular injections in psoriatic arthritis which involves synovial membrane growth complicated in psoriatic patients and leads to bone destruction, non-steroidal antiinflammatory agents and analgesic agents in intervertebral disc disease in which destruction of extracellular matrix of the intervertebral disk is observed, and non-steroidal antiinflammatory agents, colchicine and the like in acute crystalline synovitis respectively (Ryumachi Gaku, compiled by Hirohata Kazushi et al., Dobun Shoin, 1989). However, such a pharmacotherapy is a symptomatic therapy, and it has hardly inhibited the destruction of joints sufficiently.
In the therapy of rheumatoid arthritis, the selection of the positive therapy to prevent the destruction of joints as much as possible is currently being accepted. The point of this therapy is that a disease is diagnosed as rheumatoid arthritis at the earliest possible stage and antirheumatic drugs such as methotrexate are properly selected. However, sufficient diagnosis has not yet been provided.
A fibroblast growth factor (hereinafter abbreviated as FGF), one of various growth factors existing in vivo, has been known as a heparin-binding growth factor that affects vascular endothelial cells. Further, the FGF family involves 19 types or more, and FGF-2 (basic FGF), FGF-1 (acidic FGF) and the like have been long known. As an FGF receptor, seven types have been to date found, and encode a tyrosine kinase in the intracellular region.
FGF-8 is a factor isolated from a culture supernatant of mouse breast cancer cell line SC-3 (Nakamura N. et al., J. Steroid Biochem., 27, 459-464, 1987) showing sex hormone-dependent growth as an androgen-induced growth factor (AIGF). It is a growth factor which is inductively produced by androgen stimulation and enhances the growth of SC-3 cells in an autocrine manner (Tanaka A. et al., Proc. Natl. Acad. Sci. USA, 89, 8928-8932, 1992). It is reported that FGF-8 accelerates the growth of cells of prostate cancer or fibroblasts (Tanaka A. et al., FEBS Lett., 363, 226-230, 1995). It is reported that FGF-8 bound to three receptors, FGF receptor-2IIIc, FGF receptor-3IIIc and FGF receptor-4 (Ornitz D. M. et al., J. Biol. Chem., 271, 15292-15297, 1996). Moreover, binding to membrane type heparan sulfate proteoglycan such as syndecan is required for the function of FGF. Binding to heparan sulfate is necessary to the stable and local accumulation of FGF. In the situation of tissue remodelingion such as inflammation, it is considered that heparan sulfate is degraded to liberate FGF from extracellular matrix to exhibit its activity. A strong angiogenesis factor such as FGF-2 is comprised in cartilages (Satoh H. et al., J. Biol. Chem., 273, 12307-12315, 1998). In the arthritis, synovial cells, chondrocytes and inflammatory cells invaded synthesize FGF-1 or FGF-2 at an extremely high level (Sano H. et al., J. Cell Biol., 110, 1417-1426, 1990, Remmers E. F., Growth factors, 2, 179-188, 1990), and the FGF-2 concentration in a synovial fluid of rheumatic patients correlates with arthritis (Manabe N. et al., Rheumatology, 38, 714-720, 1999). FGF-2 is involved in osteophyte formation in osteoarthritis (Uchino M. et al., Clin. Orthop., 377, 119-125, 2000). These reports prove that FGF-1 or FGF-2 is involved in arthritis.
In the report using FGF-8 knockout mice, FGF-8 expressed at the stage of the development of joints (Haraguchi R. et al., Development, 127, 2471-2479, 2000; Lewandoski M. et al., Nat. Genet., 26, 460-463, 2000). Nevertheless, it is unknown that FGF-8 is involved in arthritis.